use-phluorin-to-assess-dynamics-axon-guidance-receptors-cell-culture

Use of pHluorin to Assess the Dynamics of Axon Guidance Receptors in Cell Culture and in the Chick Embryo

During development, axon guidance receptors play a crucial role in regulating axons sensitivity to both attractive and repulsive cues. Indeed, activation ...

modeling-charcot-marie-tooth-disease-vitro-transfecting-mouse-primary

Modeling Charcot-Marie-Tooth Disease <em>In Vitro</em> by Transfecting Mouse Primary Motoneurons

Neurodegeneration of spinal motoneurons (MNs) is implicated in a large spectrum of neurological disorders including amyotrophic lateral sclerosis, ...

University of Lyon

Université Lyon

Hospices Civils de Lyon

Recessive mutations in alsin, a guanine-nucleotide exchange factor for the GTPases Rab5 and Rac1, cause juvenile amyotrophic lateral sclerosis (ALS2) and related motoneuron disorders. Alsin function in motoneurons remained unclear because alsin knock-out mice do not develop overt signs of motoneuron degeneration.

Alsin/Rac1 signaling controls survival and growth of spinal motoneurons.

Charcot-Marie-Tooth (CMT) disorders are a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies characterized by muscle weakness and wasting, foot and hand deformities, and electrophysiological changes. The CMT4H subtype is an autosomal recessive demyelinating form of CMT that was recently mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin, by homozygosity mapping. We report here the identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in both families. FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GTP)-binding proteins (Rho GTPases). Rho GTPases play a key role in regulating signal-transduction pathways in eukaryotes. In particular, they have a pivotal role in mediating actin cytoskeleton changes during cell migration, morphogenesis, polarization, and division. Consistent with these reported functions, expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN. To our knowledge, this is the first report of mutations in a Rho GEF protein being involved in CMT.

Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H.

Indices of neuroinflammation are found in a variety of diseases of the CNS including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Over the years, neuroinflammation, in degenerative disorders of the CNS, has evolved from being regarded as an innocent bystander accomplishing its housekeeping function secondary to neurodegeneration to being considered as a bona fide contributor to the disease process and, in some situations, as a putative initiator of the disease. Herein, we will review neuroinflammation in both ALS and SMA not only from the angle of neuropathology but also from the angle of its potential role in the pathogenesis and treatment of these two dreadful paralytic disorders.

Inflammation in ALS and SMA: sorting out the good from the evil.

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are among the most common motor neuron diseases to afflict the human population. A deficiency of the survival of motor neuron (SMN) protein causes SMA and is also reported to be an exacerbating factor in the development of ALS. However, pathways linking the two diseases have yet to be defined and it is not clear precisely how the pathology of ALS is aggravated by reduced SMN or whether mutant proteins underlying familial forms of ALS interfere with SMN-related biochemical pathways to exacerbate the neurodegenerative process. In this study, we show that mutant superoxide dismutase-1 (SOD1), a cause of familial ALS, profoundly alters the sub-cellular localization of the SMN protein, preventing the formation of nuclear 'gems' by disrupting the recruitment of the protein to Cajal bodies. Overexpressing the SMN protein in mutant SOD1 mice, a model of familial ALS, alleviates this phenomenon, most likely in a cell-autonomous manner, and significantly mitigates the loss of motor neurons in the spinal cord and in culture dishes. In the mice, the onset of the neuromuscular phenotype is delayed and motor function enhanced, suggestive of a therapeutic benefit for ALS patients treated with agents that augment the SMN protein. Nevertheless, this finding is tempered by an inability to prolong survival, a limitation most likely imposed by the inexorable denervation that characterizes ALS and eventually disrupts the neuromuscular synapses even in the presence of increased SMN.

Mutant superoxide dismutase 1 (SOD1), a cause of amyotrophic lateral sclerosis, disrupts the recruitment of SMN, the spinal muscular atrophy protein to nuclear Cajal bodies.

Arnaud Jacquier

University Claude Bernard Lyon1,
CGphiMC UMR CNRS 5534,
University Claude Bernard Lyon1, CGphiMC UMR CNRS 5534

University of Lyon

Use of pHluorin to Assess the Dynamics of Axon Guidance Receptors in Cell Culture and in the Chick Embryo

Modeling Charcot-Marie-Tooth Disease In Vitro by Transfecting Mouse Primary Motoneurons

Arnaud Jacquier

University Claude Bernard Lyon1,CGphiMC UMR CNRS 5534,University Claude Bernard Lyon1, CGphiMC UMR CNRS 5534

University of Lyon

Use of pHluorin to Assess the Dynamics of Axon Guidance Receptors in Cell Culture and in the Chick Embryo

Modeling Charcot-Marie-Tooth Disease In Vitro by Transfecting Mouse Primary Motoneurons

University Claude Bernard Lyon1,
CGphiMC UMR CNRS 5534,
University Claude Bernard Lyon1, CGphiMC UMR CNRS 5534